Cost-Effective, Safe, and Personalized Cell Therapy for Critical Limb Ischemia in Type 2 Diabetes Mellitus

Abstract

Cell therapy is a progressively growing field that is rapidly moving from preclinical model development to clinical application. Outcomes obtained from clinical trials reveal the therapeutic potential of stem cell-based therapy to deal with unmet medical treatment needs for several disorders with no therapeutic options. Among adult stem cells, mesenchymal stem cells (MSCs) are the leading cell type used in advanced therapies for the treatment of autoimmune, inflammatory and vascular diseases. To date, the safety and feasibility of autologous MSC-based therapy has been established; however, their indiscriminate use has resulted in mixed outcomes in preclinical and clinical studies. While MSCs derived from diverse tissues share common properties depending on the type of clinical application, they markedly differ within clinical trials in terms of efficacy, resulting in many unanswered questions regarding the application of MSCs. Additionally, our experience in clinical trials related to critical limb ischemia pathology (CLI) shows that the therapeutic efficacy of these cells in different animal models has only been partially reproduced in humans through clinical trials. Therefore, it is crucial to develop new research to identify pitfalls, to optimize procedures and to clarify the repair mechanisms used by these cells, as well as to be able to offer a next generation of stem cell that can be routinely used in a cost-effective and safe manner in stem cell-based therapies targeting CLI.

Multi-Parameter Analysis of Biobanked Human Bone Marrow Stromal Cells Shows Little Influence for Donor Age and Mild Comorbidities on Phenotypic and Functional Properties

“…However, this has to be interpreted with caution since the number of donors with multiple comorbidities in this analysis was very limited due to their rare occurrence in our biobank. Indeed, changes in BMSC transcriptome upon disease progression to a more advanced stage (e.g., in advanced insulin-dependent diabetes and renal failure) have been reported earlier (55, 58, 60).…”

“…Our PCA of RNA-sequencing-derived gene expression profiles of unstimulated resting BMSC samples at early passage (P3) showed no clear separation between adult vs. elderly or non-diabetic vs. early-stage diabetic donors (both analysis of the whole cohort n = 14 vs. 7 or for the sub-stratified analysis of elderly non-diabetics vs. elderly diabetics n = 6 each). We compared non-diabetic vs. diabetic donors, since this was the most common and well-defined comorbidity in our cohort and is also frequently studied by others (60).…”

Mesenchymal Stromal Cell Therapeutic Delivery: Translational Challenges to Clinical Application

“…A recent Cochrane analysis of autologous cells treatments, including bone marrow (BM)-MSCs, for CLI found no differences between IA and IM deliveries (42). Furthermore, Soria et al found that IM delivery may be superior to IA delivery regarding the mitigation of adipose tissue (AT)-derived MSCs prothrombotic properties (43). Interestingly, work by Lataillade et al has also shown promising effects of local IM-injections of MSCs in dosimetry-guided surgery treatment of radiations burns (44), while both, local IM and systemic IV delivery of MSCs and MSC-like cells has led to rescue from lethal radiation in animal models (45, 46).…”

Improved therapeutics of modified mesenchymal stem cells: an update

“…The introduction of cell therapy has made dramatic contribution to science and continue to expand in value and utility in regenerative medicine and disease therapeutics. Experimental and clinical applications of cell therapy has covered many diseases including cardiovascular conditions [1][2][3], Parkinson's disease [4,5], osteoarthritis [6], diabetes [7,8], neurological conditions [9], wounds [10], malignancies [11], among others. The special characteristic properties of MSCs have been exploited in countless research field with fascinating outcomes.…”